This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background &Aims: The Gastrointestinal tract (GIT) is a major target of HIV/SIV infection. Although our understanding of HIV/SIV enteropathy has greatly improved, the recent discovery of miRNAs has added yet another novel and complex regulator of gene expression with potential roles in the molecular pathogenesis of this disorder. MicroRNAs (miRNAs) are genomically transcribed, ~21-23 nucleotide noncoding RNAs that are highly conserved and suppress gene expression by targeting miRNAs for translational repression or degradation. We investigated the contribution of 7 miRNAs to GIT disease and inflammation using the SIV-infected rhesus macaque model. Methods: Colon tissue was collected at necropsy from 9 SIV-infected (G1) with chronic diarrhea and 3 uninfected control macaques (G2). The contributions of miR-21, miR-125b, miR-132, miR-146a, miR-155, miR-212, miR-223 and miR-338 previously known to be associated with inflammation were investigated using QRT-PCR, In situ hybridization/Immunofluorescence and histopathology. Results: All G1 macaques had chronic diarrhea, wasting and colitis. Significant to moderate increase in the expression of miR-212 (4-fold), miR-21, miR-125b and miR-223 (2-fold) was observed in the colon of G1 macaques compared to G2 animals. No change in miR-132, miR-146a, miR-155 and miR-338 expression was observed between the groups. In situ hybridization using Locked-nucleic acid modified miR-212 probes revealed cytoplasmic and nuclear localization in the colonic epithelium and lamina propria cells (macrophages). Using TargetScan4.2 and PicTar we identified several putative miRNA-212 targets with potential roles in intestinal function and inflammation. Conclusion: Our findings suggest that deregulation in cell/tissue-specific expression of miRNAs occurring in response to HIV/SIV infection may disrupt the functional relationship between the intestinal epithelium and the mucosal immune system causing alterations in intestinal structure and function.